Millions of workers are routinely exposed to metal- working fluids (MWF) when these complex chemical mixtures are sprayed on metal as it is machined. Growing evidence suggests that there are carcinogenic effects of at least some types of MWF. In particular, the largest study of exposed workers yet conducted (a study of 46,000 United Automobile Workers/General Motors employees) has found strongly increased risks of laryngeal and esophageal carcinomas. The goal of the proposed work is to substantially expand the epidemiologic evidence linking MWF to cancers of the upper aerodigestive tract by a series of statistical studies using the UAW/GM data set. These analyses are designed to clarify several important outstanding issues which currently limit conclusions on the risk from these widespread industrial chemicals. This project will: 1. Estimate cancer risks from exposure to MWF for the upper aerodigestive tract, not by traditional organ designations (larynx and esophagus, for example), but by groupings which correspond more closely to routes of exposure and likely target tissues for exogenous chemicals: epilarynx and hypopharynx (both inhalation and ingestion); endolarynx (exposure by inhalation); and esophagus excluding adenocarcinoma of the esophagogastric junction (primarily ingestion); 2. Evaluate the magnitude of potential confounding by tobacco and alcohol in this cohort (which lacks individual data on these risk factors) by using the method of indirect adjustment; and 3. Apply the Moolgavkar-Knudson two-stage cancer model to the quantitative MWF exposure data to provide a biologically-based method to investigate the temporal (early versus late stage) contribution of different types and components of MWF to cancer risks in the upper aerodigestive tract. In addition to addressing the specific issue of metalworking fluids and cancer, this project will also contribute more generally to environmental cancer epidemiology by demonstrating the feasibility of incorporating more sophisticated, biologically-based, modeling methods into the widely used retrospective cohort study.